BackgroundA significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms.Methods and ResultsSixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented.SignificanceThese data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk.
Cardiac disease in adult female carriers of the X-linked dystrophinopathies, Duchenne and Becker muscular dystrophies, is a wellrecognised entity. A single study has reported a 15% incidence of cardiac abnormalities in female carriers under 16 years. Our study aims, clinically and with electrocardiograph and echocardiograph, to determine the incidence of cardiac abnormality in young girls who are proven carriers of X-linked dystrophinopathies. Twenty-three girls aged 6.2-15.9 years were assessed. All had normal cardiac examination. None had electrocardiograph abnormalities consistent with dystrophic cardiomyopathy. Left ventricular fractional shortening ranged from 33 to 55% (normal . 28%). Septal thickness, posterior wall thickness and wall thickness ratio were within normal limits. No cardiac abnormalities have been demonstrated in young girls who are proven carriers of X-linked dystrophinopathies in our study. This has important implications for planning timing of carrier determination and cardiac assessment. q
There are significant clinical benefits to be gained from a combined mutation detection protocol for carrier detection. It is recommended that mutation-specific carrier frequencies for the different classes of dystrophin mutations should be taken into account in genetic counselling practice.
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